The incidence and prevalence of congestive heart failure (CHF) in the United States is becoming a national public health problem due to the unprecedented growth of the aging population. In order to improve the health and quality of life of individuals at risk for developing the devastating effects of CHF, new strategies to prevent or delay the onset of predisposing conditions are needed to reduce the escalating morbidity and mortality associated with this disease. One of the important causes of cardiac dysfunction in patients suffering from CHF is the development of hypertrophic cardiomyopathy (HCM), a genetically heterogeneous disease of the heart characterized by left ventricular hypertrophy and impaired contractile function. Mutations in the gene encoding the cardiac isoform of myosin-binding protein C (cMyBP-C) are one of the most common causes of HCM. The mechanisms by which mutant cMyBP-C contribute to the pathogenesis of this disease, however, are not well established and require further investigation into the functional roles of cMyBP-C in myocardial contraction and the resulting deficits that occur following the disruption of cMyBP-C expression. The purpose of this proposal is to study the cellular and molecular processes that are involved in the the development and progression of contractile dysfunction in cMyBP-C associated HCM. To do this, mechanical measurements performed on mouse myocardium carrying constitutive or inducible cMyBP-C null mutations will be used to study the changes in contractile function that occur as a function of age. Concurrent changes in protein expression, structure, and function at the myofibrillar level will also be investigated utilizing proteomic approaches to study the molecular mechanisms underlying the pathogenesis of contractile dysfunction in HCM, as well as the potential contributions of compensatory mechanisms. The specific aims of this proposal will be to: (1) investigate the compensatory processes underlying contractile function in cMyBP-C homozygous null mice, (2) assess the progression of contractile dysfunction following functional compensation in cMyBP-C homozygous null mice, and (3) characterize the development of contractile dysfunction in transgenic mice conditionally expressing the cMyBP-C null allele. Relevance to Public Health: Heart failure is predominately a disease of the elderly that accounts for the majority of deaths in the United States. The purpose of this proposal is to study the underlying processes that lead to the downstream development and progression of heart failure. The results of these studies will help identify new strategies to prevent, delay, or slow the progression of this disease.